U.S. Pat. No. 5,312,924 discloses a variety of phenylacetic acid benzylamide derivatives and their salts, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. These compounds are hypoglycemic agents. Among them, Repaglinide, (S)-(+)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]amino carbonylmethyl]benzoic acid, is an oral blood glucose-lowering drug of the meglitinide class, used in the management of type 2 diabetes mellitus (also known as non-insulin dependent diabetes mellitus or NIDDM). Repaglinide lowers blood glucose levels by stimulating the release of insulin from the pancreas. This action of Repaglinide is dependent upon functioning beta (β) cells in the pancreatic islets.
Insulin release is glucose-dependent and diminishes at low glucose concentrations. Repaglinide is represented by the following structural formula:

Various processes for the preparation of Repaglinide and related compounds are disclosed in U.S. Pat. No. 5,312,924, PCT Publication Nos. WO 03/027072 A1 and WO 2004/103983 A1, and U.S. Patent Application No. 2007/0123564 A1.
In the preparation of Repaglinide, ethyl (S)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoate of formula I(i):

is a key intermediate. According to U.S. Pat. No. 5,312,924 (hereinafter referred to as the '924 patent), the compound of formula I(i) can be prepared by the reaction of (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine with 3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid in the presence of a dehydrating agent. The dehydrating agents include ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N′-dicyclohexylcarbodiimide, N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N′-carbonyldiimidazole or N,N′-thionyldiimidazole or triphenylphosphine/carbon tetrachloride. The reaction is performed optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine, in a solvent such as methylene chloride at a temperature of −25° C. to 250° C., preferably −10° C. to the boiling temperature of the solvent used, to produce ethyl (S)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoate of formula I(i). The compound of formula I(i) is then subjected to hydrolysis in the presence of an acid or a base to produce Repaglinide.
Repaglinide obtained by the processes described in the '924 patent is generally not of satisfactory purity. Unacceptable amounts of impurities are formed during the reaction between (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid, thus resulting in a poor product yield. The process has the following disadvantages and limitations:                i) the reagent N,N′-carbonyldiimidazole is expensive, highly moisture sensitive and yields are generally very low (50-60%);        ii) the use of a triphenylphosphine/carbon tetrachloride combination results in an impure product, which requires multiple purification steps by re-crystallization or column chromatography. Also carbon tetrachloride is hazardous to ecosystems and human health;        iii) the use of N,N′-dicyclohexylcarbodiimidazole (DCC) generates N, N′-dicyclohexyl urea (DCU) as by-product, which cannot be removed easily from the product. Also, N,N′-dicyclohexylcarbodiimidazole (DCC) is toxic and it is not advisable to use in a commercial scale reaction.        
According to PCT Publication No. WO 03/027072 A1 (hereinafter referred to as the '072 application), the compound of formula I(i) is prepared by the reaction of (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine with 3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid in the presence of pivaloyl chloride and a base.
The process used in the '072 application suffers from disadvantages such as probable racemization and high cost of reagents, the use of additional reagents such as base, low yields of the product, extra purification steps to obtain the final product, repeated crystallization and health hazards. The process is not advisable for scale up operations.
According to PCT Publication No. WO 2004/103983 A1 (hereinafter referred to as the '983 application), the compound of formula I(i) is prepared by the reaction of (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine with 3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid in the presence of propane phosphonic acid anhydride.
The process used in the '983 application suffers from disadvantages such as high cost, use of additional reagents such as bases, extra purification steps to obtain the final product, multiple crystallizations, and explosive and hazardous reagents. Moreover, the Repaglinide obtained by the process described in this application does not have satisfactory purity. The use of propane phosphonic acid anhydride is not advisable for scale up operations.
Based on the aforementioned drawbacks, the prior art processes may be unsuitable for preparation of Repaglinide in commercial scale operations.
A need remains for an improved and commercially viable process of preparing a substantially pure compound of formula I(i), to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation. Desirable process properties include non-hazardous and environmentally friendly reagents, reduced cost, greater simplicity, increased purity, and increased yield of the product, thereby enabling the production of Repaglinide and its pharmaceutically acceptable acid or base addition salts in high purity and in high yield.